23/07/2021 clusianone and cancer - Search Results - PubMed

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Molecules. 2019 Dec 3;24(23):4415.

doi: 10.3390/molecules24234415.

7- epi-Clusianone, a Multi-Targeting Natural Product with Potential

Chemotherapeutic, Immune-Modulating, and Anti-Angiogenic Properties
Wesley F Taylor  1 , Maria Yanez  1 , Sara E Moghadam  1 , Mahdi Moridi Farimani  2 , Sara Soroury  3 , Samad N Ebrahimi  2 , Marzieh Tabefam  2 , 
Ehsan Jabbarzadeh  1   4

Affiliations
PMID:
31816878
PMCID:
PMC6930650
DOI:
10.3390/molecules24234415
Free PMC article

Abstract
Targeted therapies have changed the treatment of cancer, giving new hope to many patients in recent years. The shortcomings of targeted
therapies including acquired resistance, limited susceptible patients, high cost, and high toxicities, have led to the necessity of combining these
therapies with other targeted or chemotherapeutic treatments. Natural products are uniquely capable of synergizing with targeted and non-
targeted anticancer regimens due to their ability to affect multiple cellular pathways simultaneously. Compounds which provide an additive
effect to the often combined immune therapies and cytotoxic chemotherapies, are exceedingly rare. These compounds would however provide a
strengthening bridge between the two treatment modalities, increasing their effectiveness and improving patient prognoses. In this study, 7-epi-
clusianone was investigated for its anticancer properties. While previous studies have suggested clusianone and its conformational isomers,
including 7-epi-clusianone, are chemotherapeutic, few cancer types have been demonstrated to exhibit sensitivity to these compounds and little
is known about the mechanism. In this study, 7-epi-clusianone was shown to inhibit the growth of 60 cancer cell types and induce significant cell
death in 25 cancer cell lines, while simultaneously modulating the immune system, inhibiting angiogenesis, and inhibiting cancer cell invasion,
making it a promising lead compound for cancer drug discovery.

Keywords:
cancer; chemotherapeutics; immunomodulation; multitargeting; natural compounds.

Conflict of interest statement

The authors declare no competing interest.

Cited by 3
articles 53
references 9
figures

Chem Biol Interact. 2014 Apr 5;212:20-9.

doi: 10.1016/j.cbi.2014.01.015.
Epub 2014 Feb 1.

Clusianone, a naturally occurring nemorosone regioisomer, uncouples rat

liver mitochondria and induces HepG2 cell death
Felippe H Z Reis  1 , Gilberto L Pardo-Andreu  2 , Yanier Nuñez-Figueredo  3 , Osmany Cuesta-Rubio  4 , Javier Marín-Prida  5 , Sérgio A Uyemura  6 , 
Carlos Curti  7 , Luciane C Alberici  7

Affiliations

https://pubmed.ncbi.nlm.nih.gov/?term=clusianone+and+cancer&format=abstract&size=100 1/6
23/07/2021 clusianone and cancer - Search Results - PubMed

PMID:
24491676
DOI:
10.1016/j.cbi.2014.01.015
Free article

Abstract
Clusianone is a member of the polycyclic polyprenylated acylphloroglucinol family of natural products; its cytotoxic mechanism is unknown.
Clusianone is a structural isomer of nemorosone, which is a mitochondrial uncoupler and a well-known cytotoxic anti-cancer agent; thus, we
addressed clusianone action at the mitochondria and its potential cytotoxic effects on cancer cells. In the HepG2 hepatocarcinoma cell line,
clusianone induced mitochondrial membrane potential dissipation, ATP depletion and phosphatidyl serine externalization; this later event is
indicative of apoptosis induction. In isolated mitochondria from rat liver, clusianone promoted protonophoric mitochondrial uncoupling. This
was evidenced by the dissipation of mitochondrial membrane potential, an increase in resting respiration, an inhibition of Ca(2+) influx,
stimulation of Ca(2+) efflux in Ca(2+)-loaded mitochondria, a decrease in ATP and NAD(P)H levels, generation of ROS, and swelling of
valinomycin-treated organelles in hyposmotic potassium acetate media. The cytotoxic and uncoupling actions of clusianone were appreciably
less than those of nemorosone, likely due to the presence of an intra-molecular hydrogen bond with the juxtaposed carbonyl group at the C15
position. Therefore, clusianone is capable of pharmacologically increasing the leakage of protons from the mitochondria and with favorable
cytotoxicity in relation to nemorosone.

Keywords:
Clusianone; HepG2 cell death; Mitochondria; Nemorosone; Protonophore; Uncoupler.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cited by 5
articles

Comparative Study
Bioorg Med Chem Lett. 2012 Oct 1;22(19):6144-7.
doi: 10.1016/j.bmcl.2012.08.023.
Epub 2012 Aug 11.

Comparison of the cytotoxic effects of enantiopure PPAPs, including

nemorosone and clusianone
Nigel S Simpkins  1 , Frank Holtrup, Vincent Rodeschini, James D Taylor, Robert Wolf

Affiliations
PMID:
22944119
DOI:
10.1016/j.bmcl.2012.08.023

Abstract
The synthesis of an unnatural polyprenylated acylphloroglucinol (PPAP), regioisomeric with nemorosone and clusianone, has been accomplished.
The separated enantiomers of this new PPAP, along with those of nemorosone and clusianone, have been screened for activity against HeLa
(cervix carcinoma), MIA-PaCa-2 (pancreatic carcinoma), and MCF7 (mamma carcinoma) cancer cell lines. All of the isomers examined gave
surprisingly similar results in the screens.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Cited by 3
articles

Graefes Arch Clin Exp Ophthalmol. 2013 Jan;251(1):279-84.

doi: 10.1007/s00417-012-2083-8.
Epub 2012 Jul 11.

Chemosensitivity of conjunctival melanoma cell lines to target-specific

chemotherapeutic agents
Henrike Westekemper  1 , Michael Freistuehler, Norbert Bornfeld, Klaus-Peter Steuhl, Max Scheulen, Ralf A Hilger

Affiliations
PMID:
22782301
DOI:
10.1007/s00417-012-2083-8

Abstract
Objective:
In conjunctival melanoma, local chemotherapy has been based so far on clinical evidence and limited to the therapy of melanoma in
situ. Our aim was to define substances that may have the potential to add to therapeutic options in extended local growth and metastatic
https://pubmed.ncbi.nlm.nih.gov/?term=clusianone+and+cancer&format=abstract&size=100 2/6
23/07/2021 clusianone and cancer - Search Results - PubMed

disease. Two conjunctival cell lines (CRMM-1 and CRMM-2) have been established from recurrent conjunctival melanoma. In this study, we
examined the chemosensitivity of these cell lines to different cytotoxic substances.

Materials and methods:

The cell lines CRMM-1 and CRMM-2 were exposed to chemotherapeutics for 24 h and the IC50 was generated.
Sulforhodamin-B assays were used for quantification of in vitro efficacy. Time of exposure and escalating concentrations of the substances were
adapted to the experimental setting.

Results:
Bortezomib, clusianone 502 (nemorosone), ranpirnase, and sorafenib were efficient in inhibiting the growth of conjunctival melanoma
cell lines. The IC50 achieved concentrations below or around 10 μM for these substances.

Conclusions:
Bortezomib, clusianone 502, ranpirnase, and sorafenib inhibited growth in conjunctival melanoma cell lines efficiently. The new
substances may be a suitable alternative for local therapy. New therapeutic options with highly specific targeted agents for metastatic disease
have to be evaluated in further experiments.

Comment in
Nemorosone and its emerging anti-neoplastic effects.
Kapoor S.
Graefes Arch Clin Exp Ophthalmol. 2013 Oct;251(10):2487. doi: 10.1007/s00417-013-2395-3. Epub 2013 Jun 12.
PMID: 23760655
No abstract available.

Cited by 5
articles 38
references

Angew Chem Int Ed Engl. 2007;46(46):8840-4.

doi: 10.1002/anie.200703886.

Differentiation of nonconventional "carbanions"-the total synthesis of

nemorosone and clusianone
Chihiro Tsukano  1 , Dionicio R Siegel, Samuel J Danishefsky

Affiliations
PMID:
17935090
DOI:
10.1002/anie.200703886

No abstract available

Cited by 14
articles

Toxicol In Vitro. 2020 Oct;68:104927.

doi: 10.1016/j.tiv.2020.104927.
Epub 2020 Jul 4.

A tetraprenylated benzophenone 7-epiclusianone induces cell cycle arrest

at G1/S transition by modulating critical regulators of cell cycle in breast
cancer cell lines
Simone da Silva Lamartine-Hanemann  1 , Guilherme Álvaro Ferreira-Silva  1 , Renato de Oliveira Horvath  1 , Roseli Soncini  1 , 
Ester Siqueira Caixeta  1 , Bianca Rocha-Sales  2 , Evandro Luís Niero  2 , Glaucia Maria Machado-Santelli  2 , Marcelo Henrique Dos Santos  3 , 
Jaqueline Carvalho de Oliveira  4 , Marta Miyazawa  5 , Marisa Ionta  6

Affiliations
PMID:
32634469
DOI:
10.1016/j.tiv.2020.104927

Abstract
Breast cancer is a complex disease and encompassing different types of tumor. Although advances in understanding of the molecular bases of
breast cancer biology, the therapeutic proposals available still are not effective. In this scenario, the present study aimed to evaluate the
mechanisms associated to antitumor activity of 7-Epiclusianone (7-Epi), a tetraprenylated benzophenone, on luminal A (MCF-7) and claudin-low
(Hs 578T) breast cancer cell lines. We found that 7-Epi efficiently inhibited cell proliferation and migration of these cells; however MCF-7 was
slightly more responsive than Hs 578T. Cell cycle analysis showed accumulation of cells at G0/G1 phase with drastic reduction of S population in
treated cultures. This effect was associated to downregulation of CDKN1A (p21) and cyclin E in both cell lines. In addition, 7-Epi reduced cyclin
https://pubmed.ncbi.nlm.nih.gov/?term=clusianone+and+cancer&format=abstract&size=100 3/6
23/07/2021 clusianone and cancer - Search Results - PubMed

D1 and p-ERK expression levels in MCF-7 cell line. Cytotoxic effect of 7-Epi on breast cancer cell lines was associated to its ability to increase
BAX/BCL-2 ratio. In conclusion, our findings showed that 7-Epi is a promising antitumor agent against breast cancer by modulating critical
regulators of the cell cycle and apoptosis.

Keywords:
7-Epiclusianone; Apoptosis; Breast cancer; Cell cycle arrest; Cyclin D1; Garcinia gardneriana.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Conflict of interest statement

Declaration of Competing Interest None.

Phytother Res. 2010 Mar;24(3):379-83.

doi: 10.1002/ptr.2954.

Antiproliferative effect of benzophenones and their influence on cathepsin

activity
Ramiro Mendonça Murata  1 , Regiane Yatsuda, Marcelo Henrique dos Santos, Luciana K Kohn, Felipe Terra Martins, Tanus Jorge Nagem, 
Severino Matias Alencar, João Ernesto de Carvalho, Pedro Luiz Rosalen

Affiliations
PMID:
19653314
DOI:
10.1002/ptr.2954

Abstract
The antiproliferative activity of two prenylated benzophenones isolated from Rheedia brasiliensis, the triprenylated garciniaphenone and the
tetraprenylated benzophenone 7-epiclusianone, was investigated against human cancer cell lines. The antiproliferative activity on melanoma
(UACC-62), breast (MCF-7), drug-resistant breast (NCI-ADR), lung/non-small cells (NCI460), ovarian (OVCAR 03), prostate (PC03), kidney (786-0),
lung (NCI-460) and tongue (CRL-1624 and CRL-1623) cancer cells was determined using spectrophotometric quantification of the cellular
protein content. The effect of these benzophenones on the activity of cathepsins B and G was also investigated. Garciniaphenone displayed
cytostatic activity in all cell lines, whereas 7-epiclusianone showed a dose-dependent cytotoxic effect. The IC(50) values for cell proliferation
revealed that 7-epiclusianone is more active than garciniaphenone against most of the cell lines. Furthermore, the antiproliferative effects
demonstrated by garciniaphenone and 7-epiclusianone were related to their cathepsin inhibiting properties. In conclusion, 7-epiclusianone is a
promising naturally occurring agent which displays multiple inhibitory effects which may be working in concert to inhibit cancer cell proliferation
in vitro. The putative pathway by which 7-epiclusianone affects cancer cell development may involve cathepsin inhibition.

(c) 2009 John Wiley & Sons, Ltd.

Cited by 7
articles

BMC Complement Altern Med. 2015 Oct 30;15:393.

doi: 10.1186/s12906-015-0911-1.

Anticancer activity of 7-epiclusianone, a benzophenone from Garcinia

brasiliensis, in glioblastoma
Leilane Sales  1 , Julia Alejandra Pezuk  2 , Kleiton Silva Borges  3 , María Sol Brassesco  4 , Carlos Alberto Scrideli  5 , Luiz Gonzaga Tone  6 , 
Marcelo Henrique dos Santos  7 , Marisa Ionta  8 , Jaqueline Carvalho de Oliveira  9

Affiliations
PMID:
26518729
PMCID:
PMC4628319
DOI:
10.1186/s12906-015-0911-1
Free PMC article

Abstract
Background:
Glioblastoma is the most common tumor of the central nervous system and one of the hardest tumors to treat. Consequently, the
search for novel therapeutic options is imperative. 7-epiclusianone, a tetraprenylated benzophenone isolated from the epicarp of the native
plant Garcinia brasiliensis, exhibits a range of biological activities but its prospect anticancer activity is underexplored. Thus, the aim of the
present study was to evaluate the influence of 7-epiclusianone on proliferation, clonogenic capacity, cell cycle progression and induction of
apoptosis in two glioblastoma cell lines (U251MG and U138MG).
https://pubmed.ncbi.nlm.nih.gov/?term=clusianone+and+cancer&format=abstract&size=100 4/6
23/07/2021 clusianone and cancer - Search Results - PubMed

Methods:
Cell viability was measured by the MTS assay; for the clonogenic assay, colonies were stained with Giemsa and counted by direct
visual inspection; For cell cycle analysis, cells were stained with propidium iodide and analyzed by cytometry; Cyclin A expression was
determined by immunoblotting; Apoptotic cell death was determined by annexin V fluorescein isothiocyanate labeling and Caspase-3 activity in
living cells.

Results:
Viability of both cell lines was drastically inhibited; moreover, the colony formation capacity was significantly reduced, demonstrating
long-term effects even after removal of the drug. 7-epiclusianone treatment at low concentrations also altered cell cycle progression, decreased
the S and G2/M populations and at higher concentrations increased the number of cells at sub-G1, in concordance with the increase of
apoptotic cells.

Conclusion:
The present study demonstrates for the first time the anticancer potential of 7-epiclusianone against glioblastoma cells, thus
meriting its further investigation as a potential therapeutic agent.

Cited by 3
articles 35
references 4
figures

Molecules. 2015 Jul 15;20(7):12804-16.

doi: 10.3390/molecules200712804.

7-Epiclusianone, a Benzophenone Extracted from Garcinia brasiliensis

(Clusiaceae), Induces Cell Cycle Arrest in G1/S Transition in A549 Cells
Marisa Ionta  1 , Guilherme A Ferreira-Silva  2 , Evandro L Niero  3 , Éderson D'Martin Costa  4 , Adam A Martens  5 , Welton Rosa  6 , 
Marisi G Soares  7 , Gláucia M Machado-Santelli  8 , João Henrique G Lago  9 , Marcelo H Santos  10

Affiliations
PMID:
26184153
PMCID:
PMC6332126
DOI:
10.3390/molecules200712804
Free PMC article

Abstract
Lung cancer is the leading cause of cancer deaths in the world. Disease stage is the most relevant factor influencing mortality. Unfortunately,
most patients are still diagnosed at an advanced stage and their five-year survival rate is only 4%. Thus, it is relevant to identify novel drugs that
can improve the treatment options for lung cancer. Natural products have been an important source for the discovery of new compounds with
pharmacological potential including antineoplastic agents. We have previously isolated a prenylated benzophenone (7-epiclusianone) from
Garcinia brasiliensis (Clusiaceae) that has several biological properties including antiproliferative activity against cancer cell lines. In continuation
with our studies, the present work aimed to investigate the mechanisms involved with antiproliferative activity of 7-epiclusianone in A549 cells.
Our data showed that 7-epiclusianone reduced the viability of A549 cells in a concentration-dependent manner (IC50 of 16.13 ± 1.12 μM). Cells
were arrested in G1/S transition and apoptosis was induced. In addition, we observed morphological changes with cytoskeleton disorganization
in consequence of the treatment. Taken together, the results showed that cell cycle arrest in G1/S transition is the main mechanism involved with
antiproliferative activity of 7-epiclusianone. Our results are promising and open up the prospect of using this compound in further anticancer in
vivo studies.

Keywords:
7-epiclusianone; Garcinia brasiliensis; antiproliferative activity; cell cycle arrest; cell death; lung cancer.

Conflict of interest statement

The authors declare no conflict of interest.

Cited by 5
articles 27
references 5
figures

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